There is currently no paraclinical investigation that accurately predicts clinical course, prognosis, or pathological subtypes of multiple sclerosis (MS). A pathogenic role has been suggested, but not formally demonstrated for myelin-specific antibodies in MS, and genetic factors that control these autoantibodies are not characterized. We propose 1. That autoantibody responses against myelin are heterogeneous, and that antigen/epitope recognition influences pathogenicity 2. That the development of pathogenic humoral immunity in MS is controlled at least in part at the genomic level, and that comprehensive autoantibody profiling in MS families may define distinct clinical phenotypes influenced by single or multiple genetic factors. 3. That studies of anti-myelin antibodies at early stages of MS have prognostic value. First, using specific antibody assays and a unique repository of MS family samples assembled by the investigators of this project, we will perform an extensive evaluation of autoantibodies against 3 major autoantigens of myelin and with an investigation of clinical relevance in MS families, and will analyze full genome screen data using autoantibody profiles as trait loci. The relationship between autoantibody titers and clinical MS phenotype (especially optico/spinal forms, and progressive forms with atrophy) will be evaluated. Second, we will correlate patterns of myelin autoantibodies with clinical and MRI outcomes in a 5 year prospective, longitudinal study of patients presenting with clinically isolated syndromes (CIS). Extensive analyses of antibody repertoires will be conducted, including specific detection of antibodies directed against conformational determinants of myelin oligodendrocyte glycoprotein (MOG), an exposed antigen of myelin that has been experimentally recognized as a target for demyelinating antibodies. Finally, we will directly evaluate the potential pathogenicity of anti-MOG antibody fractions purified from serum of CIS patients in vivo, using passive antibody transfer experiments in a primate MS model. These studies will provide new paraclinical markers for the subtyping and prognosis of MS, and will guide the implementation of antibody based therapies that are in development for CNS demyelinating disorders.